Harnessing Cascade Suzuki-Cyclization Reactions of Pyrazolo[3,4-b]pyridine for the Synthesis of Tetracyclic Fused Heteroaromatics

Article abstract of DOI:10.1002/ejoc.201601242

Numerous procedures have been described for the functionalization of pyrazolo[3,4-b]pyridine, mainly involving nucleophilic substitutions at the C-4 position or esterifications/amidations at the C-5 position. In this paper, we describe a robust, easy to implement protocol for the Suzuki cross-coupling reaction of chloroarene 2, followed by in-situ lactonization to provide chromenopyrazolopyridines. The extension of the scope of the reaction to fused naphthyridinones is also reported. This strategy gave access to 10 original pyrazolopyridine-containing tetracyclic compounds.

Full text of DOI:10.1002/ejoc.201601242

A Journal of
Accepted Article
Title: Harnessing cascade Suzuki-cyclization reactions of pyrazolo[3,4-
b]pyridine for the synthesis of tetracyclic fused heteroaromatics
Authors: Hubert Lavrard and Florence Popowycz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601242
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601242
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10.1002/ejoc.201601242
European Journal of Organic Chemistry
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Harnessing cascade Suzuki-cyclization reactions of pyrazolo[3,4-
b]pyridine for the synthesis of tetracyclic fused heteroaromatics
Hubert Lavrard,[a] Florence Popowycz*[a]
Abstract: Numerous procedures have been described for the
functionalization of pyrazolo[3,4-b]pyridine, mainly nucleophilic
substitutions on C-4 position and esterifications/amidations on C-5
position. Thus, we report herein a robust, easy to implement protocol
for the Suzuki cross-coupling reaction of the chloroarene 2, followed
by in situ lactonisation to provide chromenopyrazolopyridines. The
extension of the scope of the reaction to fused naphthyridinones is
also reported. This strategy granted the access to ten original
pyrazolopyridine-embedded tetracyclic compounds.
nicotinic acid.13 Some noteworthy improvements to these
syntheses have been attained in this field, namely with the use
of chromenones or isoflavones as Michael acceptors,14
multicomponent reactions,15 or hetero-Diels-Alder/microwave
induced reactions.16 In specific cases, the pyrazolo[3,4-
b]pyridine pattern is inserted in more complex polycyclic
molecular systems.14a,15a Among them, the Gould-Jacobs
reaction17 represents a high-yielding, easily scalable, user-
friendly synthesis starting from inexpensive materials, which
gives access to the 4-chloro-pyrazolo[3,4-b]pyridine 2. A four
step synthesis (Scheme 1) starting from the condensation of
phenylhydrazine with ethyl 2-cyano-3-ethoxyacrylate, followed
by an acidic mediated decarboxylation afforded 5-aminopyrazole
1. Subsequent addition on diethyl ethoxymethylenemalonate
followed by chlorinative cyclization in POCl3 afforded 4-chloro-
pyrazolo[3,4-b]pyridine 2 in 64% for 4 steps.
Introduction
Over the years, the pyrazolo[3,4-b]pyridine has emerged as a
multivalent scaffold involved in numerous pharmaceutically
active compounds. A broad range of medicinal compounds such
as analgesics,1 anti-inflammatories,2 vasodilators,3 anxiolytics,4
anti-diabetics,5 anti-tumoral agents,6
anti-retroviral7or anti-
leishmanial8 molecules display this moiety, which is structurally
related to purine bases9 and allopurinol.10 Such biological
importance, along with the availability of pyrazolo[3,4-b]pyridines
anxiolytic drugs like cartazolate, etazolate, tracazolate, BAY 41-
2272 cardiovascular therapeutic11 or GSK-3 inhibitor (Figure 1)
make them desirable compounds for the screening of new
biological activities.
Scheme 1. Gould-Jacobs synthesis of pyrazolo[3,4-b]pyridine.
Despite the already proven prevalence of the pyrazolo[3,4-
b]pyridine scaffold, very few synthetic methods have been
reported for the introduction of molecular diversity at the C-4
position on derivative 2. The only published examples being
classical nucleophilic substitutions with a broad range of
alcohols, amines, anilines, or hydrazines18 apart from one patent
by Jablonski which describes the sole example of a Suzuki
cross-coupling reaction on a similar substrate.19 Due to the
cooperative electron-withdrawing effects of the intracyclic
nitrogen and the ester moiety, the C-Cl bond is weakened, and
prone to oxidative addition on transition metal complexes, which
usually needs electron-rich ligands or harsh reaction
conditions.20 Therefore, application of the Suzuki cross-coupling
reaction21 with this chloropyridine moiety would afford an
interesting functionalization method.
Figure 1. Biologically active pyrazolo[3,4-b]pyridines
In addition to their wide potential, synthesis of the pyrazolo[3,4-
b]pyridine core is usually straightforward, relying on
condensation reactions of either 1,3-dicarbonyl or ,-
unsaturated carbonyl compounds with 5-aminopyrazoles,12 or
cyclization of hydrazines with properly-substituted derivatives of
[a]
H. Lavrard, F. Popowycz
Université Lyon, Institut National des Sciences Appliquées,
Université Claude BernardLyon1, CNRS, ICBMS, UMR 5246, 20,
Avenue Albert Einstein, F-69621, Villeurbanne, France.
E-mail: florence.popowycz@insa-lyon.fr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601242
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Results and Discussion
mild and phosphine-free Suzuki reaction, bis(dicyclohexylamine)
palladium diacetate25 (DAPCy) was tried as a catalyst, affording
excellent yields (Table 1, entry 6).
Some cross-coupling reactions on activated chloroheteroarenes
have been already successful.22 Our preliminary experiments
focused on three sets of cross-coupling conditions (Table 1)
which were already described. The medium yields (77-84%)
obtained by Jablonski19 under standard conditions (toluene,
EtOH, 5 mol% Pd(PPh3)4) seemed surprisingly low. When these
conditions were re-evaluated on the simple phenylboronic acid
(Table 1, entry 1), the reactions were unreproducible, and yields
down to 70%. Although no dehalogenation product 5 was
observed, the main impurity was the ether product 6 coming
from nucleophilic substitution on C-4 position by ethanol. Since
the lability of the chlorine atom was hampering the coupling
reaction, replacement of EtOH by less nucleophilic tBuOH
increased the yield up to 97% (Table1, entry 4), without any
trace of ether side product 6.
Table 1. Pyrazolo[3,4-b]pyridines in Suzuki cross-coupling
Entry
1
3a
Catalyst
Base
Solvent
Temp
75°C
Yield
70%
5 mol%
Toluene
1.2 eq.
Na2CO3
Pd(PPh3)4
EtOH/water
2 mol%
Toluene
2
3
4
5
6
1.2 eq.
1.2 eq.
1.2 eq.
1.2 eq.
1.5 eq.
Na2CO3
Na2CO3
Na2CO3
K2CO3
75°C
75°C
63%
57%
Pd(PPh3)4
EtOH/water
1 mol%
Toluene
Pd(PPh3)4
EtOH/water
5 mol%
Toluene
tBuOH/water
75°C
97%
Pd(PPh3)4
5 mol%
DME/water
Dioxane
100°C
100°C
5 (86%)
97%
Pd(PPh3)4
5 mol%
DAPCy
Cs2CO3
Scheme 2. Extension of the Suzuki reaction with substituted boronic acids
The Gronowitz conditions,23 which were successful with electron
deficient chloropyridine22a-b and with hindered boronic acids24
were also tested (Table 1, entry 5), affording dehalogenated
compound 5 (86%) as the sole product. Intending to perform a
With those two sets of conditions in hand, we tried to further
expand the scope of this reaction. Unfortunately, while
expanding our scope, the DAPCy catalyst proved to be less
versatile than Pd(PPh3)4 under the studied conditions. No
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10.1002/ejoc.201601242
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conversion was observed with electron-deficient or sterically
hindered boronic acid, like 3h, 3j and 3p. Therefore, the
modified Jablonski’s conditions were retained for the scope
(Table 1, entry 4).
Almost all para-substituted boronic acids (Scheme 2) could be
smoothly coupled to the pyrazolopyridine moiety, with excellent
yields. The meta-substituted compounds furnished also
satisfying yields. Challenging ortho-substituted boronic acids
afforded good yields, with the only exception of much hindered
3r and 3x. Despite these excellent results, limitations were
observed in the case of 4-bromophenylboronic acid which
resulted in an intractable mixture of products – probably due to
oligomerization of the reagent under these conditions – and the
mesitylboronic acid, indisputably predictable due to high steric
hindrance.
Scheme 4. Domino Suzuki – cyclization
In addition to the good yields furnished by this domino reaction,
no intermediate or by-product could be detected within the
reaction medium.
However, owing to the limited availability of substituted 2-
hydroxyphenylboronic acids, the polycyclic compounds were
prepared from the Suzuki products 4t-x, which were
demethylated with BBr3 according to standard procedures.26
Therefore, intramolecular transesterification occurred more or
less smoothly and, in certain cases, might need the use of
azeotropic distillation of water (Table 2).
Surprisingly, no conversion was detected with 4-
hydroxyphenylboronic acid under the optimized conditions
(Scheme 3). We assumed that the use of sodium carbonate
resulted in the formation of the dianionic conjugated base of 4-
hydroxyphenylboronic acid, which low solubility in toluene
inhibited the reaction. Changing Na2CO3 by Na2HPO4 and
adding 1 equivalent of tertbutylammonium bromide provided the
expected product in 46% yield with a partial conversion of 50%.
Table 2. Cyclization of Suzuki adducts
Entry
Starting material (R =)
4t (H)
Third step[a]
Product (yield[b], %)
7a (86)
1
2
no
no
4u (5-F)
7b (94)
3
4v (4-F)
yes
no
7c (53)
4
4w (5-iPr)
7d (83)
Scheme 3. Suzuki coupling of 2 with 4-hydroxyphenyl boronic acid
5
4x (2-methoxynaphtalen-1-yl)
yes
7e (64)
[a]
Azeotropic distillation of water using a Dean-Stark apparatus. [b]Yields
When using boronic acid ortho-substituted with a nucleophilic
moiety,
like
2-hydroxyphenylboronic
acid
or
2-
calculated on the pure isolated products.
aminophenylboronic acid, a tandem Suzuki cross-coupling /
cyclization occurred leading to tetracyclic derivatives 7a and 8a
with good to excellent yields (Scheme 4). There is a noteworthy
The same difficulties were addressed for the preparation of
derivatives of 8a. A family of compound 8a has been patented
by Pierre Fabre in 2012 as antineoplastic agent, with a
completely different methodology.27 Since substituted 2-
aminophenylboronic acids are not available, an alternate
synthesis was considered. N-Boc protected boronic acids were
prepared through ortho-lithiation of protected anilines.
Investigation of the Suzuki coupling directly on N-Boc protected
boronic acid 11a was first investigated (Table 3). Optimized
conditions used on 2-N-Boc-aminophenylboronic acid led to a
mixture of three products: starting material 2 (22%), Suzuki
adduct 9a (33%), Suzuki / cyclization product 10a (45%) (Table
3, entry 1). Increasing the load of Pd to 7 or 10 mol% did not
affect the conversion but compound 9a was always the major
product (Table 3, entries 2 and 3). Total conversion was
observed with 1.5 equivalent of boronic acid instead of 1.2
equivalents (Table 3, entries 4-6) and the best conditions (Table
difference
between
the
reactivity
of
2-
and
4-
hydroxyphenylboronic acid. The ortho-substituted reagent
behaves classically under our standard conditions without the
need of additional weaker base or TBAB. This could be
explained by the existence of an intramolecular hydrogen bond
between the phenol and the acid moiety. Second deprotonation
of the stabilized 2-hydroxyphenylboronate is disfavoured leading
to a monoanionic species displaying much more affinity with the
organic phase, allowing thus the cross-coupling reaction.
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10.1002/ejoc.201601242
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3, entry 4) were retained for the coupling step. Unfortunately,
isolation of the three different products was difficult in most of
the cases due to solubility or separation issues. Since 8a was
the only compound of interest, the crude mixture obtained after
the cross-coupling step was simply treated with TFA, converting
simultaneously 9a and 10a to 8a. Tetracyclic derivative 8a was
finally isolated in yields ranging from 71% to 78% in two steps
(Scheme 5).
Experimental Section
Reagents and solvents were supplied by Aldrich, Acros, Lancaster, Alfa
Aesar, Fluka or TCI and purchased at the highest commercial quality to
be used without further purification. NMR spectra were recorded on a
Brüker 300 (1H: 300 MHz; 13C: 75 MHz; 19F: 282 MHz), Bruker 400 (1H:
400 MHz; 13C: 100 MHz; 19F: 376 MHz) spectrometers at 298 K, using
CDCl3, DMSO-d6, and TFA-d as solvents. The chemical shifts (δ, ppm)
are referenced to the residual solvent peak and coupling constants (J)
are reported in the standard fashion. Chemical shifts reference for 19F
was CFCl3. The following abbreviations are used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, hept. =
heptuplet, m = multiplet, br = broad, app. = apparent. Electrospray
ionization (ESI) mass spectrometry (MS) experiments were performed on
a Thermo Finnigan LCQ Advantage mass spectrometer. High-resolution
mass spectra (HRMS) were recorded on a Finnigan Mat 95xL mass
spectrometer using either the electrospray (ESI) or atmospheric pressure
chemical
ionization
(APCI)
technique.
Analytical
thin-layer
chromatography was carried out on silica gel Merck 60 D254 (0.25 mm).
Flash chromatography was performed on Merck Si 60 silica gel (40–63
μm). Infra-red (IR) spectra were recorded with an IRAffinity-1 Shimadzu
spectrometer using attenuated total reflectance (ATRMiracle), and the
wavenumbers were expressed in cm–1. Melting points were measured
using Büchi apparatus B-540.
Table 3. Optimization of coupling with ortho-NHBoc boronic acid
Preparations of products 4a-x: In a round-bottom flask, compound 2
(150 mg, 0.497 mmol, 1 eq.), Pd(PPh3)4 (29 mg, 5 mol%), boronic acid
3a-x (0.596 mmol, 1.2 eq.), and Na2CO3 (105 mg, 0.998 mmol, 2 eq.)
were weighed, and carefully purged with Ar. Degassed toluene (3 mL),
tBuOH (1.5 mL), and water (0.5 mL) were added, and the solution was
heated at 75°C for 5-18 hours. The crude mixture was cooled down to
room temperature, diluted with a saturated aqueous solution of Na2CO3
(10 mL), and extracted with CH2Cl2 (3x20 mL). The organic layers were
combined, washed with brine (10 mL), dried over Na2SO4, and
evaporated under reduced pressure. Flash chromatography on silica gel
(pentane/EtOAc 95:5 to 80:20) afforded pure products.
Entry
Boronic acid
Pd(PPh3)4
Conversion[a]
9a[a]
10a[a]
8a[a]
1
2
3
4
5
6
1.2 eq.
1.2 eq.
1.2 eq.
1.5 eq.
1.5 eq.
1.5 eq.
5 mol%
7 mol%
10 mol%
5 mol%
7 mol%
10 mol%
78%
80%
33%
60%
53%
58%
66%
80%
45%
20%
29%
36%
28%
12%
0%
0%
0%
6%
6%
8%
82%
100%
100%
100%
Ethyl 1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4a):
white powder, 97%, m.p.: 91°C. IR: 1701, 1587, 1502, 1369, 1307, 1257,
1153. 1H-NMR (300 MHz, CDCl3): δ = 9.16 (s, 1H), 8.26 (dd, 2H, J = 8.7
Hz, J = 1.1 Hz), 8.05 (s, 1H), 7.59-7.51 (m, 5H), 7.47-7.44 (m, 2H), 7.36
(tt, 1H, J = 7.4 Hz, J = 1.1 Hz), 4.18 (q, 2H, J = 7.1 Hz), 1.06 (t, 3H, J =
7.1 Hz). 13C-NMR (75 MHz, CDCl3): δ = 166.8 (Cq), 151.6 (CH), 150.8
(Cq), 146.8 (Cq), 139.2 (Cq), 136.3 (Cq), 135.2 (CH), 129.3 (2 CH), 129.0
(CH), 128.6 (2 CH), 128.5 (2 CH), 126.8 (CH), 121.8 (2 CH), 120.1 (Cq),
117.5 (Cq), 61.3 (CH2), 13.8 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for
C21H18N3O2: 344.1394; found: 344.1390.
[a] NMR ratios
Ethyl
4-(4-methylphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4b): white crystals, 94%, m.p.: 100°C. IR: 2912, 1701,
1583, 1504, 1421, 1365, 1313, 1259, 1151, 1020, 983, 798, 754, 736.
1H-NMR (300 MHz, DMSO-d6): δ = 8.97 (s, 1H), 8.25 (s, 1H), 8.22 (dd,
2H, J = 8.0 Hz, J = 1.1 Hz), 7.58 (t, 2H, J = 8.0 Hz), 7.41-7.34 (m, 5H),
4.11 (q, 2H, J = 7.1 Hz), 2.41 (s, 3H), 1.01 (t, 3H, J = 7.1 Hz). 13C-NMR
(75 MHz, DMSO-d6): δ = 166.3 (Cq), 150.6 (CH), 150.1 (Cq), 145.7 (Cq),
138.7 (Cq), 138.6 (Cq), 135.3 (CH), 132.3 (Cq), 129.3 (2 CH), 129.1 (2
CH), 128.6 (2 CH), 126.6 (CH), 121.0 (2 CH), 120.3 (Cq), 116.5 (Cq), 61.0
(CH2), 20.9 (CH3), 13.5 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for
C22H20N3O2: 358.1550; found: 358.1554.
Scheme 5. Two-step Suzuki – cyclization
Conclusion
In conclusion, we have developed a robust practical protocol for
the cross-coupling of 4-chloro-pyrazolo[3,4-b]pyridine, affording
biphenyl products in excellent yields. Capitalizing on this
methodology, a family of 10 tetracyclic fused products was
obtained with satisfying yields in the presence of ortho-hydroxyl
or ortho-amino substituted phenylboronic acids.
Ethyl 4-([1,1’-biphenyl]-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4c): white powder, 96%, m.p.: 131°C. IR: 2993, 1697, 1573,
1
1502, 1313, 1259, 1151, 756, 732. H-NMR (300 MHz, CDCl3): δ = 9.18
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1
(s, 1H), 8.28 (dd, 2H, J = 8.6 Hz, J = 1.1 Hz), 8.13 (s, 1H), 7.77 (d, 2H, J
= 8.4 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.60-7.48 (m, 6H), 7.44-7.35 (m, 2H),
4.22 (q, 2H, J = 7.1 Hz), 1.11 (t, 3H, J = 7.1 Hz). 13C-NMR (75 MHz,
CDCl3): δ = 166.9 (Cq), 151.6 (CH), 150.8 (Cq), 146.5 (Cq), 141.9 (Cq),
140.4 (Cq), 139.2 (Cq), 135.2 (CH), 135.1 (Cq), 129.3 (2 CH), 129.2 (2
CH), 129.1 (2 CH), 127.9 (CH), 127.3 (2 CH), 127.2 (2 CH), 126.8 (CH),
121.8 (2 CH), 120.1 (Cq), 117.5 (Cq), 61.4 (CH2), 13.9 (CH3). HRMS-ESI:
m/z [M+H]+ calcd. for C27H22N3O2: 420.1707; found: 420.1695.
1309, 1261, 1168, 798, 752, 740. H-NMR (300 MHz, CDCl3): δ = 10.14
(s, 1H), 9.23 (s, 1H), 8.24 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.05 (d, 2H, J
= 8.2 Hz), 7.96 (s, 1H), 7.62 (d, 2H, J = 8.2 Hz), 7.56 (dd, 2H, J = 8.5 Hz,
J = 7.5 Hz), 7.37 (tt, 1H, J = 7.5 Hz, J = 1.1 Hz), 4.19 (q, 2H, J = 7.1 Hz),
1.09 (t, 3H, J = 7.1 Hz). 13C-NMR (75 MHz, CDCl3): δ = 191.8 (CH),
166.0 (Cq), 151.8 (CH), 150.7 (Cq), 145.5 (Cq), 142.5 (Cq), 138.9 (Cq),
136.4 (Cq), 134.7 (CH), 129.7 (2 CH), 129.4 (2 CH), 129.3 (2 CH), 127.0
(CH), 121.8 (2 CH), 119.4 (Cq), 117.2 (Cq), 61.5 (CH2), 13.9 (CH3).
HRMS-ESI: m/z [M+H]+ calcd. for C22H18N3O3: 372.1343; found:
372.1324.
Ethyl
4-(4-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4d): white crystals, 95%, m.p.: 139°C. IR: 3068, 2978,
1
1707, 1581, 1500, 1317, 1232, 1161, 796, 758, 736. H-NMR (300 MHz,
Ethyl
4-(4-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
CDCl3): δ = 9.16 (s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.02 (s,
1H), 7.56 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.47-7.42 (m, 2H), 7.37 (tt, 1H,
J = 7.5 Hz, J = 1.1 Hz), 7.26-7.20 (m, 2H), 4.21 (q, 2H, J = 7.1 Hz), 1.13
(t, 3H, J = 7.1 Hz). 13C-NMR (75 MHz, CDCl3): δ = 166.5 (Cq), 163.3 (d,
J = 249 Hz, Cq), 151.7 (CH), 150.7 (Cq), 145.8 (Cq), 139.1 (Cq), 134.9
(CH), 132.2 (d, J = 4 Hz, Cq), 130.5 (d, J = 8 Hz, 2 CH), 129.3 (2 CH),
126.9 (CH), 121.8 (2 CH), 120.0 (Cq), 117.6 (Cq), 115.7 (d, J = 22 Hz, 2
CH), 61.4 (CH2), 14.0 (CH3). 19F-NMR (282 MHz, CDCl3): δ = -112.79.
HRMS-ESI: m/z [M+Na]+ calcd. for C21H16FN3NaO2: 384.1119; found:
384.1110.
carboxylate (4i): white crystals, 96%, m.p.: 155°C. IR: 1710, 1577, 1516,
1500, 1348, 1336, 1307, 1259, 1151, 1134, 983, 852, 800, 756, 738. H-
1
NMR (400 MHz, CDCl3): δ = 9.26 (s, 1H), 8.40 (dt, 2H, J = 8.8 Hz, J = 2.2
Hz), 8.24 (dd, 2H, J = 8.6 Hz, J = 1.1 Hz), 7.93 (s, 1H), 7.62 (dt, 2H, J =
8.8 Hz, J = 2.2 Hz), 7.56 (dd, 2H, J = 8.6 Hz, J = 7.5 Hz), 7.38 (tt, 1H, J =
7.5 Hz, J = 1.1 Hz), 4.22 (q, 2H, J = 7.1 Hz), 1.15 (t, 3H, J = 7.1 Hz). 13C-
NMR (100 MHz, CDCl3): δ = 165.6 (Cq), 151.9 (CH), 150.7 (Cq), 148.1
(Cq), 144.5 (Cq), 143.0 (Cq), 138.9 (Cq), 134.4 (CH), 129.5 (2 CH), 129.4
(2 CH), 127.1 (CH), 123.7 (2 CH), 121.8 (2 CH), 119.1 (Cq), 117.1 (Cq),
61.6 (CH2), 14.0 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for C21H17N4O4:
389.1244; found: 389.1242.
Ethyl
4-(4-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4e): white powder, 93%, m.p.: 109°C. IR: 2978, 1712, 1581,
1496, 1423, 1313, 1165, 1087, 829, 796, 723. 1H-NMR (400 MHz,
CDCl3): δ = 9.18 (s, 1H), 8.24 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.00 (s,
1H), 7.56 (t, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.51 (dt, 2H, J = 8.5 Hz, J = 2.1
Hz), 7.40 (dt, 2H, J = 8.5 Hz, J = 2.1 Hz), 7.37 (tt, 1H, J = 7.5 Hz, J = 1.1
Hz), 4.21 (q, 2H, J = 7.1 Hz), 1.14 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz,
CDCl3): δ = 166.4 (Cq), 151.7 (CH), 150.7 (Cq), 145.6 (Cq), 139.0 (Cq),
135.2 (Cq), 134.8 (CH), 134.7 (Cq), 129.9 (2 CH), 129.3 (2 CH), 128.8 (2
CH), 126.9 (CH), 121.8 (2 CH), 119.7 (Cq), 117.4 (Cq), 61.5 (CH2), 14.0
(CH3). HRMS-ESI: m/z [M+H]+ calcd. for C21H17ClN3O2: 378.1004; found:
378.0994.
Ethyl
1-phenyl-4-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4j): white powder, 97%, m.p.: 178°C. IR: 1708, 1581, 1494,
1315, 1261, 1166, 985, 752. 1H-NMR (400 MHz, CDCl3): δ = 9.23 (s, 1H),
8.79 (bs, 2H), 8.23 (dd, 2H, J = 8.0 Hz, J = 1.0 Hz), 7.94 (s, 1H), 7.55 (t,
2H, J = 8.0 Hz), 7.38-7.34 (m, 3H), 4.19 (q, 2H, J = 7.1 Hz), 1.09 (t, 3H, J
= 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ = 165.7 (Cq), 151.8 (CH), 150.7
(Cq), 149.9 (2 CH), 144.5 (Cq), 143.8 (Cq), 138.9 (Cq), 134.4 (CH), 129.3
(2 CH), 127.0 (CH), 123.1 (2 CH), 121.7 (2 CH), 119.0 (Cq), 116.8 (Cq),
61.6 (CH2), 13.8 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for C20H17N4O2:
345.1346; found: 345.1344.
Ethyl
4-(3-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
Ethyl
4-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4k): white powder, 97%, m.p.: 125°C. IR: 1695, 1575, 1498,
1311, 1163, 1016, 756. 1H-NMR (400 MHz, CDCl3): δ = 9.18 (s, 1H),
8.24 (dd, 2H, J = 8.5 Hz, J = 1.5 Hz), 8.02 (s, 1H), 7.55 (dd, 2H, J = 8.5
Hz, J = 7.5 Hz), 7.48 (td, 1H, J = 8.0 Hz, J = 5.8 Hz), 7.36 (t, 1H, J = 7.5
Hz, J = 1.1 Hz), 7.24-7.16 (m, 3H), 4.20 (q, 2H, J = 7.1 Hz), 1.10 (t, 3H, J
= 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ = 166.3 (Cq), 162.6 (d,
J = 247 Hz, CF), 151.6 (CH), 150.7 (Cq), 145.2 (d, J = 2 Hz, Cq), 139.0
(Cq), 138.3 (d, J = 8 Hz, Cq), 134.8 (CH), 130.2 (d, J = 9 Hz, CH), 129.3
(2 CH), 126.9 (CH), 124.3 (d, J = 3 Hz, CH), 121.7 (2 CH), 119.8 (Cq),
117.3 (Cq), 115.9 (d, J = 21 Hz, CH), 115.8 (d, J = 23 Hz, CH), 61.4
(CH2), 13.8 (CH3). 19F-NMR (282 MHz, CDCl3): δ = -113.06. HRMS-ESI:
m/z [M+H]+ calcd. for C21H17FN3O2: 362.1299; found: 362.1311.
carboxylate (4f): white powder, 97%, m.p.: 80°C. IR: 2974, 1722, 1583,
1502, 1423, 1298, 1228, 1168, 1028, 827, 798, 750, 729. 1H-NMR (400
MHz, CDCl3): δ = 9.11 (s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.0 Hz), 8.09
(s, 1H), 7.55 (dd, 2H, J = 8.5 Hz, 7.5 Hz), 7.42 (d, 2H, J = 8.7 Hz), 7.35
(tt, 1H, J = 7.5 Hz, 1.1 Hz), 7.06 (d, 2H, J = 8.7 Hz), 4.22 (q, 2H, J = 7.1
Hz), 3.90 (s, 3H), 1.14 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ
= 167.1 (Cq), 160.4 (Cq), 151.5 (CH), 150.8 (Cq), 146.5 (Cq), 139.2 (Cq),
135.2 (CH), 130.2 (2 CH), 129.3 (2 CH), 128.3 (Cq), 126.7 (CH), 121.7 (2
CH), 120.1 (Cq), 117.5 (Cq), 114.0 (2 CH), 61.3 (CH2), 55.5 (CH3), 14.0
(CH3). HRMS-ESI: m/z [M+H]+ calcd. for C22H20N3O3: 374.1499; found:
374.1494.
Ethyl
1-phenyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-
Ethyl
4-(3-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
b]pyridine-5-carboxylate (4g): white powder, 93%, m.p.: 124°C. IR:
1693, 1583, 1502, 1319, 1263, 1161, 1134, 1066, 840, 800, 752, 734.
1H-NMR (300 MHz, CDCl3): δ = 9.23 (s, 1H), 8.25 (dd, 2H, J = 8.6 Hz, J
= 1.1 Hz), 7.80 (d, 2H, J = 8.1 Hz), 7.59-7.54 (m, 4H), 7.38 (tt, 1H, J = 7.4
Hz, J = 1.1 Hz), 4.19 (q, 2H, J = 7.1 Hz), 1.09 (t, 3H, J = 7.1 Hz). 13C-
NMR (75 MHz, CDCl3): δ = 166.1 (Cq), 151.8 (CH), 150.7 (Cq), 145.3 (Cq),
140.1 (Cq), 139.0 (Cq), 134.7 (CH), 131.1 (q, J = 33 Hz, Cq), 129.4 (2 CH),
128.9 (2 CH), 127.0 (CH), 125.5 (q, J = 4 Hz, 2 CH), 124.1 (q, J = 272 Hz,
CF3), 121.8 (2 CH), 119.6 (Cq), 117.4 (Cq), 61.5 (CH2), 13.8 (CH3). 19F-
NMR (282 MHz, CDCl3): δ = -63.12. HRMS-ESI: m/z [M+H]+ calcd. for
C22H17F3N3O2: 412.1267; found: 412.1260.
carboxylate (4l): white powder, 98%, m.p.: 133°C. IR: 1708, 1581, 1497,
1368, 1308, 1258, 1164, 983, 786. H-NMR (400 MHz, CDCl3): δ = 9.19
1
(s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.01 (s, 1H), 7.55 (dd, 2H,
J = 8.5 Hz, J = 7.5 Hz), 7.51-7.44 (m, 3H), 7.36 (tt, 1H, J = 7.5 Hz,
J = 1.1 Hz), 7.33 (dt, 1H, J = 7.1 Hz, J = 1.6 Hz), 4.20 (q, 2H, J = 7.1 Hz),
1.11 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ = 166.3 (Cq),
151.7 (CH), 150.7 (Cq), 145.1 (Cq), 139.0 (Cq), 138.0 (Cq), 134.8 (CH),
134.4 (Cq), 129.8 (CH), 129.3 (2 CH), 129.0 (CH), 128.6 (CH), 126.9
(CH), 126.7 (CH), 121.7 (2 CH), 119.7 (Cq), 117.3 (Cq), 61.4 (CH2), 13.9
(CH3). HRMS-ESI: m/z [M+H]+ calcd. for C21H17ClN3O2: 378.1004; found:
378.1004.
Ethyl
4-(4-formylphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
Ethyl
4-(3-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4h): white powder, 99%, m.p.: 122°C. IR: 1693, 1581, 1502,
carboxylate (4m): white powder, 95%, m.p.: 95°C. IR: 1697, 1577, 1315,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601242
European Journal of Organic Chemistry
FULL PAPER
1244, 1159, 1018, 785, 754, 690. 1H-NMR (400 MHz, CDCl3): δ = 9.13 (s,
1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.07 (s, 1H), 7.55 (dd, 2H, J =
8.5 Hz, J = 7.5 Hz), 7.43 (t, 1H, J = 7.9 Hz), 7.36 (tt, 1H, J = 7.5 Hz, J =
1.1 Hz), 7.06-7.02 (m, 2H), 7.00-6.99 (m, 1H), 4.19 (q, 2H, J = 7.1 Hz),
3.86 (s, 3H), 1.09 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ =
166.8 (Cq), 159.6 (Cq), 151.4 (CH), 150.7 (Cq), 146.5 (Cq), 139.1 (Cq),
137.5 (Cq), 135.2 (CH), 129.6 (CH), 129.3 (2 CH), 126.8 (CH), 121.7 (2
CH), 121.0 (CH), 120.2 (Cq), 117.4 (Cq), 114.4 (CH), 114.2 (CH), 61.3
(CH2), 55.5 (CH3), 13.9 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for
C22H20N3O3: 374.1499; found: 374.1501.
(CH2), 13.9 (CH3). 19F-NMR (282 MHz, CDCl3): δ = -115.01. HRMS-ESI:
m/z [M+H]+ calcd. for C21H17FN3O2: 362.1299; found: 362.1295.
Ethyl
1-phenyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4r): white crystals, 64%, m.p.: 90°C. IR: 1726,
1498, 1311, 1168, 1103, 1031. 898, 754, 534, 1H-NMR (400 MHz,
CDCl3): δ = 9.34 (s, 1H), 8.27 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 7.85 (d,
1H, J = 7.4 Hz), 7.79 (s, 1H), 7.70-7.61 (m, 2H), 7.56 (dd, 2H, J = 8.5 Hz,
J = 7.5 Hz), 7.37 (tt, 1H, J = 7.5 Hz, J = 1.1 Hz), 7.32 (d, 1H, J = 7.0 Hz),
4.12 (q, 2H, J = 7.1 Hz), 1.00 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz,
CDCl3): δ = 165.4 (Cq), 151.9 (CH), 150.5 (Cq), 144.4 (Cq), 139.0 (Cq),
135.3 (q, J = 2.1 Hz, Cq), 135.0 (CH), 131.6 (CH), 129.7 (CH), 129.4 (2
CH), 128.7 (CH), 128.0 (q, J = 31 Hz, Cq), 126.9 (CH), 126.3 (q,
J = 4.9 Hz, CH), 123.9 (q, J = 274 Hz, CF3), 121.7 (2 CH), 119.6 (Cq),
118.1 (Cq), 61.1 (CH2), 13.7 (CH3). 19F-NMR (282 MHz, CDCl3): δ = -
59.61. HRMS-ESI: m/z [M+H]+ calcd. for C22H17F3N3O2: 412.1267; found:
412.1262.
Ethyl
4-(3,5-bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4n): white crystals, 98%, m.p.: 128°C. IR:
1698, 1576, 1314, 1273, 1190, 1162, 1125, 1108, 896, 799, 706. 1H-
NMR (400 MHz, CDCl3): δ = 9.30 (s, 1H), 8.24 (dd, 2H, J = 8.5 Hz,
J = 1.1 Hz), 8.05 (bs, 1H), 7.94 (s, 1H), 7.91 (bs, 2H), 7.57 (dd, 2H,
J = 8.5 Hz, J = 7.5 Hz), 7.40 (tt, 1H, J = 7.5 Hz, J = 1.1 Hz), 4.20 (q, 2H,
J = 7.1 Hz), 1.09 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ =
165.5 (Cq), 152.2 (CH), 150.8 (Cq), 143.3 (Cq), 138.8 (Cq), 138.6 (Cq),
134.2 (CH), 132.0 (q, J = 34 Hz, 2 Cq), 129.4 (2 CH), 128.9 (q, J = 3 Hz,
2 CH), 127.2 (CH), 123.2 (q, J = 273 Hz, 2 CF3), 122.7 (vquint., J = 4 Hz,
CH), 121.9 (2 CH), 119.3 (Cq), 117.2 (Cq), 61.7 (CH2), 13.8 (CH3). 19F-
NMR (282 MHz, CDCl3): δ = -63.28. HRMS-ESI: m/z [M+H]+ calcd. for
C23H16F6N3O2: 480.1141; found: 480.1128.
Ethyl
4-(2-formylphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4s): white powder, 95%, m.p.: 105°C. IR: 1689, 1583, 1311,
1153, 985, 758, 638. 1H-NMR (400 MHz, CDCl3): δ = 9.81 (s, 1H), 9.33
(s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.10 (dd, 1H, J = 7.5 Hz, J
= 1.3 Hz), 7.79 (s, 1H), 7.74 (td, 1H, J = 7.5 Hz, J = 1.5 Hz), 7.68 (td, 1H,
J = 7.5 Hz, J = 1.3 Hz), 7.56 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.40-7.33
(m, 2H), 4.13 (q, 2H, J = 7.1 Hz), 1.05 (t, 3H, J = 7.1 Hz). 13C-NMR (100
MHz, CDCl3): δ = 190.6 (CH), 165.4 (Cq), 151.9 (CH), 150.6 (Cq), 144.4
(Cq), 138.91 (Cq), 138.86 (Cq), 134.8 (CH), 133.8 (Cq), 133.7 (CH),
129.54 (CH), 129.45 (CH), 129.4 (2 CH), 129.3 (CH), 127.0 (CH), 121.8
(2 CH), 119.8 (Cq), 118.3 (Cq), 61.4 (CH2), 13.8 (CH3). HRMS-ESI: m/z
[M+H]+ calcd. for C22H18N3O3: 372.1343; found: 372.1341.
Ethyl
4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4o): purified on flash column chromatography with pure
CH2Cl2 as the eluent, white powder, 90%, m.p.: 152°C. IR: 1709, 1579,
1
1529, 1500, 1348, 1315, 1262, 1143, 797. H-NMR (400 MHz, CDCl3): δ
= 9.27 (s, 1H), 8.38 (ddd, 1H, J = 7.9 Hz, J = 2.3 Hz, J = 1.4 Hz), 8.33
(dd, 1H, J = 2.3 Hz, J = 1.4 Hz), 8.24 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz),
7.95 (s, 1H), 7.78 (dt, 1H, J = 7.9 Hz, J = 1.4 Hz), 7.72 (t, 1H, J = 7.9 Hz),
7.56 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.37 (tt, 1H, J = 7.5 Hz, J = 1.1 Hz),
4.22 (q, 2H, J = 7.1 Hz), 1.14 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz,
CDCl3): δ = 165.6 (Cq), 152.0 (CH), 150.7 (Cq), 148.2 (Cq), 144.2 (Cq),
138.9 (Cq), 137.9 (Cq), 134.5 (CH), 134.4 (CH), 129.5 (CH), 129.3 (2 CH),
127.1 (CH), 123.73 (CH), 123.69 (CH), 121.8 (2 CH), 119.2 (Cq), 117.3
(Cq), 61.6 (CH2), 14.0 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for
C21H17N4O4: 389.1244; found: 389.1240.
Ethyl
4-(2-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4t): off-white powder, 97%, m.p.: 110°C. IR: 1720, 1585,
1
1490, 1417, 1288, 1242, 1157, 1028, 889, 800, 744. H-NMR (400 MHz,
CDCl3): δ = 9.16 (s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.02 (s,
1H), 7.55 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.48 (ddd, 1H, J = 8.3 Hz, J =
7.5 Hz, J = 1.7 Hz), 7.39-7.33 (m, 2H), 7.14 (td, 1H, J = 7.5 Hz, J = 0.9
Hz), 7.03 (d, 1H, J = 8.3 Hz), 4.17 (q, 2H, J = 7.1 Hz), 3.75 (s, 3H) 1.08 (t,
3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ = 166.7 (Cq), 156.3 (Cq),
151.2 (CH), 151.1 (Cq), 143.3 (Cq), 139.2 (Cq), 135.4 (CH), 130.5 (CH),
129.9 (CH), 129.3 (2 CH), 126.7 (CH), 125.3 (Cq), 121.7 (2 CH), 121.1
(Cq), 120.8 (CH), 117.8 (Cq), 110.8 (CH), 61.0 (CH2), 55.5 (CH3), 13.9
(CH3). HRMS-ESI: m/z [M+Na]+ calcd. for C22H19NaN3O3: 396.1319;
found: 396.1304.
Ethyl
4-(2-methylphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4p): colorless oil, 100%. IR: 1708, 1583, 1500, 1311, 1155,
891, 754, 729. 1H-NMR (400 MHz, CDCl3): δ = 9.28 (s, 1H), 8.28 (dd, 2H,
J = 8.5 Hz, J = 1.1 Hz), 7.86 (s, 1H), 7.56 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz),
7.41-7.29 (m, 4H), 7.17 (dd, 1H, J = 7.5 Hz, J = 1.2 Hz), 4.14 (q, 2H, J =
7.1 Hz), 1.02 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ = 166.1
(Cq), 151.8 (CH), 150.7 (Cq), 147.1 (Cq), 139.1 (Cq), 136.2 (Cq), 135.3
(CH), 135.0 (Cq), 130.0 (CH), 129.3 (2 CH), 128.6 (CH), 127.8 (CH),
126.7 (CH), 125.6 (CH), 121.6 (2 CH), 120.0 (Cq), 117.8 (Cq), 61.1 (CH2),
19.9 (CH3), 13.7 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for C22H20N3O2:
358.1550; found: 358.1555.
Ethyl
4-(5-fluoro-2-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4u): white powder, 98%, m.p.: 116°C. IR:
1718, 1498, 1244, 1157, 1029, 922, 744. 1H-NMR (400 MHz, CDCl3): δ =
9.19 (s, 1H), 8.26 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.01 (s, 1H), 7.55 (dd,
2H, J = 8.5 Hz, J = 7.5 Hz), 7.36 (tt, 1H, J = 7.5 Hz, J = 1.1 Hz), 7.17
(ddd, 1H, J = 9.0 Hz, J = 8.0 Hz, J = 3.1 Hz), 7.11 (dd, 1H, J = 8.3 Hz, J =
3.1 Hz), 6.95 (dd, 1H, J = 9.0 Hz, J = 4.3 Hz), 4.20 (q, 2H, J = 7.1 Hz),
3.71 (s, 3H), 1.13 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz, CDCl3): δ =
166.4 (Cq), 157.0 (d, J = 240 Hz, CF), 152.5 (d, J = 2 Hz, Cq), 151.3 (CH),
151.1 (Cq), 141.9 (d, J = 2 Hz, Cq), 139.2 (Cq), 135.0 (CH), 129.3 (2 CH),
126.8 (CH), 126.6 (d, J = 8 Hz, Cq), 121.8 (2 CH), 120.9 (Cq), 117.5 (Cq),
116.8 (d, J = 25 Hz, CH), 116.3 (d, J = 23 Hz, CH), 111.8 (d, J = 8 Hz,
CH), 61.2 (CH2), 56.1 (CH3), 14.0 (CH3). 19F-NMR (376 MHz, CDCl3): δ =
-123.97. HRMS-ESI: m/z [M+Na]+ calcd. for C22H18FN3NaO3: 414.1224;
found: 414.1218.
Ethyl
4-(2-fluorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (4q): white powder, 98%, m.p.: 92°C. IR: 1709, 1585, 1504,
1313, 1255, 1149, 1016, 987, 894, 756, 534. 1H-NMR (400 MHz, CDCl3):
δ = 9.27 (s, 1H), 8.26 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.01 (s, 1H), 7.56
(dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.52-7.50 (m, 1H), 7.45 (td, 1H, J = 7.4
Hz, J = 1.7 Hz), 7.39-7.31 (m, 2H), 7.23 (t, 1H, J = 9.1 Hz), 4.23 (qd, 2H,
J = 7.1 Hz, J = 3.7 Hz), 1.13 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz,
CDCl3): δ = 166.0 (Cq), 159.4 (d, J = 248 Hz, CF), 151.8 (CH), 151.0 (Cq),
140.6 (Cq), 139.1 (Cq), 135.0 (CH), 131.0 (d, J = 8 Hz, CH), 130.3 (d,
J = 3 Hz, CH), 129.4 (2 CH), 126.9 (CH), 124.3 (d, J = 3 Hz, CH), 124.2
(Cq), 121.8 (2 CH), 120.3 (Cq), 117.7 (Cq), 115.9 (d, J = 21 Hz, CH), 61.4
Ethyl
4-(4-fluoro-2-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4v): white powder, 98%, m.p.: 109°C. IR:
1724, 1500, 1276, 1176, 1026, 948, 842, 767, 694. 1H-NMR (400 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601242
European Journal of Organic Chemistry
FULL PAPER
CDCl3): δ = 9.16 (s, 1H), 8.25 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 7.99 (s,
1H), 7.55 (dd, 2H, J = 8.5 Hz, J = 7.5 Hz), 7.37-7.31 (m, 2H), 6.85 (vtd,
1H, J = 8.2 Hz, J = 2.4 Hz), 6.76 (dd, 1H, J = 11 Hz, J = 2.3 Hz), 4.20 (q,
2H, J = 7.1 Hz), 3.73 (s, 3H), 1.14 (t, 3H, J = 7.1 Hz). 13C-NMR (100 MHz,
CDCl3): δ = 166.6 (Cq), 164.4 (d, J = 249 Hz, CF), 157.7 (d, J = 10 Hz,
Cq), 151.3 (CH), 151.1 (Cq), 142.4 (Cq), 139.2 (Cq), 135.1 (CH), 130.7 (d,
J = 10 Hz, CH), 129.3 (2 CH), 126.7 (CH), 121.7 (2 CH), 121.2 (d,
J = 3 Hz, Cq), 121.0 (Cq), 117.8 (Cq), 107.4 (d, J = 22 Hz, CH), 99.5 (d,
J = 26 Hz, CH), 61.1 (CH2), 55.8 (CH3), 14.0 (CH3). 19F-NMR (282 MHz,
CDCl3): δ = -109.67. HRMS-ESI: m/z [M+H]+ calcd. for C22H19FN3O3:
392.1405; found: 392.1405.
TFA-d):  = 9.93 (s, 1H), 9.56 (s, 1H), 8.93 (d, 1H, J = 8.0 Hz), 8.04 (t, 1H,
J = 8.0 Hz), 7.78 (t, 1H, J = 8.0 Hz), 7.75-7.69 (m, 5H), 7.67 (d, 1H,
J = 8.0 Hz). 13C-NMR (100 MHz, TFA-d):  = 163.5 (Cq), 149.1 (Cq),
147.8 (CH), 143.0 (Cq), 141.8 (Cq), 140.2 (CH), 139.6 (CH), 135.8 (Cq),
134.4 (CH), 132.9 (2 CH), 130.7 (CH), 128.9 (CH), 127.4 (2 CH), 120.6
(CH), 117.9 (Cq), 117.8 (Cq), 117.0 (Cq). HRMS-APCI: m/z [M+H]+ calcd.
for C19H13N4O: 313.1084; found: 313.1084.
Preparation of chromenone derivatives 7a-7e through BBr3
cyclization: To a solution of 4t-4x (0.14 mmol) in CH2Cl2 (0.8 mL) was
added BBr3 (4 eq., 560 μL, 1M solution in CH2Cl2). After stirring at room
temperature for 18 hours, a KOH solution (20 eq., 2M in water) was
added, and stirred for 15 minutes. The organic and aqueous layers were
separated, and the latter was extracted with CH2Cl2 (3 x 50mL). The
combined organic layers were dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo. The product was purified by flash column
chromatography (SiO2, pure EtOAc or CH2Cl2/MeOH 9:1).
In the case of compounds 7c and 7e, the same procedure was followed
at the beginning. After stirring at room temperature for 18 hours, water (2
mL) and toluene (10 mL) were added, and heated at reflux with a Dean-
Stark apparatus for 18 h. Concentration of the crude mixture, followed by
purification by flash column chromatography (SiO2, pure EtOAc or
CH2Cl2/MeOH 9:1) afforded the expected compounds.
Ethyl
4-(5-isopropyl-2-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4w): colorless oil, 96%. IR: 2956, 1712, 1500,
1244, 1159, 1206, 754, 690. 1H-NMR (400 MHz, CDCl3): δ = 9.14 (s, 1H),
8.26 (dd, 2H, J = 8.5 Hz, J = 1.5 Hz), 8.04 (s, 1H), 7.55 (dd, 2H, J = 8.5
Hz, J = 7.5 Hz), 7.37-7.31 (m, 2H), 7.24 (d, 1H, J = 2.3 Hz), 6.94 (d, 1H,
J = 8.5 Hz), 4.17 (q, 2H, J = 7.1 Hz), 3.73 (s, 3H), 2.96 (hept., 1H, J = 6.9
Hz), 1.30 (d, 3H, J = 6.9 Hz), 1.29 (d, 3H, J = 6.9 Hz), 1.06 (t, 3H, J = 7.1
Hz). 13C-NMR (100 MHz, CDCl3): δ = 166.9 (Cq), 154.3 (Cq), 151.1 (Cq),
151.0 (CH), 143.5 (Cq), 141.2 (Cq), 139.2 (Cq), 135.5 (CH), 129.3 (2 CH),
128.2 (CH), 128.0 (CH), 126.6 (CH), 124.9 (Cq), 121.7 (2 CH), 121.3 (Cq),
117.7 (Cq), 110.7 (CH), 61.0 (CH2), 55.6 (CH3), 33.4 (CH), 24.4 (CH3),
24.2 (CH3), 13.8 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for C25H26N3O3:
416.1969; found: 416.1962.
3-Phenylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one (7a): white
powder, 86%.
Ethyl
4-(2-methoxynaphthalen-1-yl)-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (4x): white powder, 46%, m.p.: 147°C. IR:
1720, 1587, 1498, 1417, 1238, 1170, 889, 806, 750, 534. H-NMR (400
10-Fluoro-3-phenylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one
(7b): white powder, 94%, m.p.: 360°C (dec.). IR: 1730, 1575, 1552, 1500,
1448, 1259, 1182, 1122, 1008, 839, 750. 1H-NMR (400 MHz, TFA-d): δ =
9.68 (s, 1H), 9.33 (s, 1H), 8.32 (dd, 1H, J = 7.9 Hz, J = 2.2 Hz), 7.74-7.66
(m, 7H). 13C-NMR (100 MHz, TFA-d): δ = 163.7 (Cq), 162.7 (d,
J = 250 Hz, CF), 152.4 (d, J = 1.6 Hz, Cq), 151.5 (CH), 147.5 (Cq), 147.0
(Cq), 138.4 (CH), 136.4 (Cq), 133.9 (CH), 132.6 (2 CH), 127.6 (2 CH),
127.1 (d, J = 25 Hz, CH), 122.9 (d, J = 8.6 Hz, CH), 117.9 (Cq), 115.5 (d,
J = 26 Hz, CH), 115.1 (Cq), 113.9 (Cq). 19F-NMR (282 MHz, DMSO-d6): δ
= -115.51. HRMS-ESI: m/z [M+H]+ calcd. for C19H11FN3O2: 332.0830;
found: 332.0832.
1
MHz, CDCl3): δ = 9.38 (s, 1H), 8.30 (dd, 2H, J = 8.5 Hz, J = 1.1 Hz), 8.02
(d, 1H, J = 9.0 Hz), 7.88 (d, 1H, J = 7.5 Hz), 7.71 (s, 1H), 7.57 (dd, 2H, J
= 8.5 Hz, J = 7.5 Hz), 7.43 (d, 1H, J = 9.0 Hz), 7.39-7.34 (m, 2H), 7.31
(ddd, 1H, J = 8.3 Hz, J = 6.8 Hz, J = 1.5 H), 7.16 (d, 1H, J = 8.3 Hz), 3.96
(q, 2H, J = 7.1 Hz), 3.82 (s, 3H), 0.72 (t, 3H, J = 7.1 Hz). 13C-NMR (100
MHz, CDCl3): δ = 166.1 (Cq), 153.3 (Cq), 152.1 (CH), 151.0 (Cq), 142.8
(Cq), 139.3 (Cq), 135.7 (CH), 132.4 (Cq), 130.6 (CH), 129.3 (2 CH), 128.9
(Cq), 128.3 (CH), 127.2 (CH), 126.7 (CH), 124.2 (CH), 124.0 (CH),
121.73 (Cq), 121.68 (2 CH), 119.2 (Cq), 118.7 (Cq), 113.1 (CH), 60.8
(CH2), 56.6 (CH3), 13.5 (CH3). HRMS-ESI: m/z [M+H]+ calcd. for
C26H22N3O3: 424.1656; found: 424.1640.
9-Fluoro-3-phenylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one
(7c): yellow powder, 53%, m.p.: 197°C. IR: 1741, 1727, 1602, 1503,
1333, 1271, 1153, 759. 1H-NMR (400 MHz, TFA-d): δ = 9.62 (s, 1H),
9.34 (s, 1H), 8.75 (dd, 1H, J = 9.0 Hz, J = 5.4 Hz), 7.62-7.57 (m, 5H),
7.39 (dd, 1H, J = 9.0 Hz, J = 6.7 Hz), 7.24 (dd, 1H, J = 8.3 Hz, J = 2.1
Hz). 13C-NMR (100 MHz, TFA-d): δ = 170.9 (d, J = 266 Hz, CF), 163.1
(Cq), 158.3 (d, J = 14 Hz, Cq), 150.5 (CH), 148.3 (Cq), 146.0 (Cq), 139.1
(CH), 136.1 (Cq), 134.2 (CH), 133.1 (d, J = 12 Hz, CH), 132.7 (2 CH),
127.6 (2 CH), 118.1 (d, J = 24 Hz, CH), 115.4 (Cq), 113.8 (d, J = 3 Hz,
Cq), 113.3 (Cq), 108.6 (d, J = 26 Hz, CH). 19F-NMR (282 MHz, TFA-d): δ
= -99.13. HRMS-ESI: m/z [M+H]+ calcd. for C19H11FN3O2: 332.0830;
found: 332.0828.
Domino preparation of tetracyclic compound 7a and 8a: In a round-
bottom flask, compound 2 (150 mg, 0.497 mmol, 1 eq.), Pd(PPh3)4 (29
mg, 5 mol%), boronic acid 3a-x (0.596 mmol, 1.2 eq.), and Na2CO3 (105
mg, 0.998 mmol, 2 eq.) were weighed, and carefully purged with Ar.
t
Degassed toluene (3 mL), BuOH (1.5 mL), and water (0.5 mL) were
added, and the solution was heated at 75°C for 18 hours. The crude
mixture was cooled to room temperature, diluted with water (10 mL) and
CH2Cl2 (10 mL), and filtered to afford the product with satisfying purity.
3-Phenylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one
(7a):
purple powder, 83%, m.p.: 250°C (dec.). IR: 1720, 1593, 1571, 1548,
1502, 1448, 1425, 1328, 1261, 1207, 1151, 981, 840, 752. 1H-NMR (400
MHz, TFA-d):  = 9.85 (s, 1H), 9.58 (s, 1H), 8.90 (d, 1H, J = 7.8 Hz), 8.13
(t, 1H, J = 7.8 Hz), 7.88 (t, 1H, J = 7.8 Hz), 7.85-7.78 (m, 5H), 7.76 (d, 1H,
J = 7.8 Hz). 13C-NMR (100 MHz, TFA-d):  = 163.4 (Cq), 156.5 (Cq),
149.7 (CH), 149.3 (Cq), 145.3 (Cq), 140.6 (CH), 139.4 (CH), 136.0 (Cq),
134.2 (CH), 132.7 (2 CH), 130.4 (CH), 129.6 (CH), 127.4 (2 CH), 121.1
(CH), 116.8 (Cq), 116.1 (Cq), 114.0 (Cq). HRMS-APCI: m/z [M+H]+ calcd.
for C19H13N3O2: 314.0924; found: 314.0919.
10-Isopropyl-3-phenylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-
one (7d): white powder, 83%, m.p.: 217°C (dec). IR: 1718, 1595, 1502,
1219, 1112, 979, 815, 750, 671. 1H-NMR (400 MHz, TFA-d): δ = 9.62 (s,
1H), 9.31 (s, 1H), 8.42 (d, 1H, J = 1.8 Hz), 7.83 (dd, 1H, J = 8.7 Hz, J =
1.8 Hz), 7.61-7.56 (m, 5H), 7.46 (d, 1H, J = 8.7 Hz), 3.11 (hept., 1H, J =
6.9 Hz), 1.31 (d, 6H, J = 6.9 Hz). 13C-NMR (100 MHz, TFA-d): δ = 163.7
(Cq), 154.9 (Cq), 152.0 (Cq), 149.8 (CH), 149.6 (Cq), 145.1 (Cq), 139.6
(CH), 139.4 (CH), 136.1 (Cq), 134.2 (CH), 132.8 (2 CH), 127.5 (2 CH),
127.5 (CH), 121.1 (CH), 116.7 (Cq), 116.2 (Cq), 114.0 (Cq), 36.1 (CH),
24.5 (2 CH3). HRMS-ESI: m/z [M+H]+ calcd. for C22H18N3O2: 356.1394;
found: 356.1395.
3-Phenyl-3H-benzo[c]pyrazolo[4,3-f][2,7]naphthyridin-6(7H)-one
(8a): purple powder, 100%, m.p.: > 365°C (dec). IR: 2879, 1680, 1595,
1575, 1504, 1421, 1342, 1292, 987, 927, 804, 742. 1H-NMR (400 MHz,
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10.1002/ejoc.201601242
European Journal of Organic Chemistry
FULL PAPER
13-Phenylbenzo[5,6]chromeno[4,3-d]pyrazolo[3,4-b]pyridin-3(13H)-
one (7e): yellow powder, 64%, m.p.: 205°C (dec). IR: 2922, 1735, 1560,
1506, 1311, 1220, 1112, 1018, 979, 750, 692, 680. 1H-NMR (400 MHz,
TFA-d): δ = 9.68 (s, 1H), 9.16 (s, 1H), 8.72 (d, 1H, J = 8.4 Hz), 8.36 (d,
1H, J = 9.0 Hz), 8.06 (d, 1H, J = 8.0 Hz), 7.81 (dd, 1H, J = 8.4 Hz, J = 7.2
Hz), 7.73 (dd, 1H, J = 8.0 Hz, J = 7.2 Hz), 7.67-7.61 (m, 5H), 7.55 (d, 1H,
J = 9.0 Hz). 13C-NMR (100 MHz, TFA-d): δ = 163.4 (Cq), 158.4 (Cq),
148.9 (Cq), 148.8 (CH), 144.5 (Cq), 143.4 (CH), 141.2 (CH), 136.0 (Cq),
134.6 (Cq), 134.3 (CH), 132.9 (2 CH), 132.11 (CH), 132.06 (CH), 131.3
(Cq), 130.6 (CH), 127.4 (2 CH), 126.9 (CH), 118.7 (CH), 117.5 (Cq),
114.3 (Cq), 112.6 (Cq). HRMS-ESI: m/z [M+H]+ calcd. for C23H14N3O2:
364.1081; found: 364.1068.
10-Methoxy-3-phenyl-3H-benzo[c]pyrazolo[4,3-f][2,7]naphthyridin-
6(7H)-one (8e): yellow powder, 78%, m.p.: 332°C. IR: 1667, 1578, 1504,
1231, 1100, 1036, 991, 815, 750. 1H-NMR (400 MHz, TFA-d): δ = 9.90 (s,
1H), 9.51 (s, 1H), 8.28 (d, 1H, J = 1.7 Hz), 7.70-7.64 (m, 7H), 4.08 (s, 3H).
13C-NMR (100 MHz, TFA-d): δ = 163.2 (Cq), 159.9 (Cq), 148.3 (CH),
148.0 (Cq), 143.2 (Cq), 139.3 (CH), 136.3 (Cq), 135.9 (Cq), 134.3 (CH),
132.9 (2 CH), 128.1 (CH), 127.4 (2 CH), 122.2 (CH), 118.8 (Cq), 117.9
(Cq), 116.8 (Cq), 113.4 (CH), 57.8 (CH3). HRMS-APCI: m/z [M+H]+ calcd
for C20H15N4O2: 343.1190; found: 343.1184.
Acknowledgements
Preparation of naphthyridinones-derivatives 8a-e: In a round-bottom
flask, compound 2 (150 mg, 0.497 mmol, 1 eq.), Pd(PPh3)4 (29 mg, 5
mol%), boronic acid 11a-e (0.746 mmol, 1.5 eq.), and Na2CO3 (210 mg,
1.966 mmol, 4 eq.) were weighed, and carefully purged with Ar.
The authors are indebted to the French ministère de la
Recherche for a grant to H.L.
t
Degassed toluene (3 mL), BuOH (1.5 mL), and water (0.5 mL) were
Keywords: pyrazolo[3,4-b]pyridine • Suzuki • tandem reaction •
chromenopyrazolopyridine • naphthyridinones
added, and the solution was heated at 75°C for 5-18 hours. The crude
mixture was cooled down to room temperature, diluted with a saturated
aqueous solution of Na2CO3 (10 mL), and extracted with CH2Cl2 (3 x 20
mL). The organic layers were combined, washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The crude mixture
was filtered on silica gel (pentane/EtOAc 80:20), evaporated, and the
crude mixture was stirred with TFA (0.2 mL) in CH2Cl2 (0.8 mL) at room
temperature for 18h. Evaporation under reduced pressure followed by
trituration in CH2Cl2 afforded the product with satisfying purity.
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1337, 1281, 1197, 951, 868, 816, 754. 1H-NMR (400 MHz, TFA-d): δ =
9.78 (s, 1H), 9.35 (s, 1H), 8.37 (dd, 1H, J = 8.4 Hz, J = 1.6 Hz), 7.61-7.54
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(CH), 138.1 (d, J = 2 Hz, Cq), 136.0 (Cq), 134.3 (CH), 132.8 (2 CH), 128.1
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C19H12FN4O: 331.0990; found: 331.0986.
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6(7H)-one (8c): white powder, 71%, m.p.: > 360°C. IR: 2867, 1677, 1592,
1573, 1501, 1424, 1332, 1007, 932, 800, 756. 1H-NMR (400 MHz, TFA-
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6(7H)-one (8d): white powder, 73%, m.p.: 358°C (dec.). IR: 2862, 1661,
1594, 1577, 1499, 1420, 1333, 985, 942, 800. 1H-NMR (400 MHz, TFA-
d): δ = 9.73 (s, 1H), 9.36 (s, 1H), 8.49 (s, 1H), 7.70 (d, 1H, J = 8.4 Hz),
7.54-7.52 (m, 5H), 7.39 (d, 1H, J = 8.4 Hz), 2.47 (s, 3H). 13C-NMR (100
MHz, TFA-d): δ = 163.5 (Cq), 148.8 (Cq), 147.9 (CH), 142.9 (Cq), 141.9
(CH), 140.4 (Cq), 139.8 (Cq), 139.6 (CH), 135.8 (Cq), 134.3 (CH), 132.9
(2 CH), 129.8 (CH), 127.4 (2 CH), 120.6 (CH), 117.9 (Cq), 117.8 (Cq),
116.9 (Cq), 21.8 (CH3). HRMS-APCI: m/z [M+H]+ calcd. for C20H15N4O:
327.1240; found: 327.1231.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601242
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201601242
European Journal of Organic Chemistry
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Heterocycles*
H. Lavrard, F. Popowycz*
Page No. – Page No.
Harnessing cascade Suzuki-
cyclization reactions of pyrazolo[3,4-
b]pyridine for the synthesis of
tetracyclic fused heteroaromatics
Preparation of chromenopyrazolopyridine and naphthyridinone families is described
from well-known intermediate 2 via a sequential Suzuki cross-coupling reaction /
acidic cyclization.
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